Endocardial HDAC3 is required for myocardial trabeculation.

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Epigenetics

Background:

• Ventricular trabeculation is crucial for heart development and function.
• Endocardial cell-derived factors regulate extracellular matrix (ECM) and growth factor secretion for trabeculation.
• Mechanisms controlling endocardial secretion in heart development are not fully understood.

Purpose of the Study:

• To investigate the role of histone deacetylase 3 (HDAC3) in endocardial cells during heart development.
• To elucidate the molecular mechanisms by which HDAC3 regulates endocardial cell function and ECM production.
• To explore the potential of targeting HDAC3 for therapeutic strategies in congenital heart disease.

Main Methods:

• Generation of endocardial-specific HDAC3 knockout mice.
• Analysis of embryonic lethality and cardiac morphology.
• Single-cell RNA sequencing of endocardial cells.
• Analysis of secreted factors (secretome) from cultured cardiac endothelial cells.
• Assessment of cardiomyocyte proliferation assays.
• Investigation of microRNA-129-5p regulation of transforming growth factor ß3 (TGF-ß3) expression.

Main Results:

• Endocardial HDAC3 knockout leads to embryonic lethality and severe ventricular hypotrabeculation.
• Single-cell RNA sequencing revealed significant downregulation of ECM components in knockout endocardial cells.
• Secretome analysis showed reduced TGF-ß3 levels and impaired cardiomyocyte proliferation, rescued by TGF-ß3.
• HDAC3 knockout upregulates TGF-ß3 by repressing microRNA-129-5p.

Conclusions:

• HDAC3 is essential for proper ventricular trabeculation by regulating endocardial ECM and growth factor secretion.
• The HDAC3/microRNA-129-5p/TGF-ß3 axis is a critical pathway in heart development.
• These findings offer insights into congenital heart disease pathogenesis and potential therapeutic targets for myocardial regeneration.